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系統識別號 U0026-0608201223030000
論文名稱(中文) 探討laminin g2 chain及laminin a5 chain 在人類口腔癌之腫瘤生成所扮演的角色
論文名稱(英文) The roles of laminin g2 chain and laminin a5 chain in the tumorigenesis of human oral cancer
校院名稱 成功大學
系所名稱(中) 生物化學暨分子生物學研究所
系所名稱(英) Department of Biochemistry and Molecular Biology
學年度 100
學期 2
出版年 101
研究生(中文) 徐美玲
研究生(英文) Mei-Ling Hsu
學號 s16984137
學位類別 碩士
語文別 中文
論文頁數 67頁
口試委員 指導教授-袁國
口試委員-吳昭良
口試委員-陳玉玲
中文關鍵字 層黏蛋白  癌症幹細胞  人類舌頭鱗狀細胞癌細胞球體  口腔癌腫瘤生成 
英文關鍵字 laminin  cancer stem cell  human tongue squamous-cell carcinoma cell (SAS) tumor sphere  oral tumorigenesis 
學科別分類
中文摘要 口腔鱗狀細胞癌(OSCC)目前已是國人第六名的癌症(衛生署最新的民國99年統計結果),也是國人男性中第四名的癌症。根據我們實驗室之前的實驗結果,我們發現癌細胞的integrin β1表現量與臨床口腔癌的分期呈現正相關性。由於laminin是integrin β1很重要的配體(ligand),且之前的文獻已經指出它與癌症有很重要的關係,但有關laminin在口腔癌的研究較少,所以我的研究主要是探討laminin g2及laminin a5在人類口腔癌之腫瘤生成中所扮演的角色。首先我利用免疫組織化學染色的方式去分析它們在病人的口腔癌組織的表現是如何,我發現laminin g2及laminin a5在高惡性癌組織的表現量比在低惡性癌組織的表現量高,且也發現只有部分癌細胞有表現laminin g2。接著以西方點墨法和免疫細胞化學染色,發現了laminin g2及laminin a5在人類舌頭鱗狀細胞癌細胞球體(SAS sphere)的表現量明顯高於SAS單層細胞(SAS monolayer)。此外,在細胞增生實驗(proliferation assay)中,我發現了laminin g2及laminin a5對於SAS的生長能力扮演很重要的角色。在抗癌藥物的細胞毒殺性實驗中,由結果發現laminin g2或laminin a5被抑制的癌細胞只有在一開始的短時間內會受藥物作用的影響而降低存活率,但隨著時間的增加,laminin g2及laminin a5的被干擾(interference)似乎會影響腫瘤微環境而促使抗藥性的產生。很多文獻指出腫瘤球體(sphere)含有較多的癌症幹細胞,再根據以上的實驗結果,我初步假設有表現laminin g2及laminin a5的癌細胞可能具有癌症幹細胞的特性。接著我以shRNA去分別抑制laminin g2及laminin a5,同時也試著以流氏細胞儀與免疫螢光染色去分析這些被抑制的細胞其癌幹細胞標記(marker)的表現情形,由結果初步發現laminin a5經由間接影響Oct-4的表現量而參與和口腔癌幹細胞有關的特性,而laminin g2則是透過間接影響CD44的表現量而參與和口腔癌幹細胞有關的特性,此實驗結果初步顯示laminin a5與laminin g2在口腔癌腫瘤生成中所扮演的角色似乎也與口腔癌幹細胞的特性有關,因為癌幹細胞的特性對於腫瘤生成也很重要,但詳細機轉仍需進一步的探究。最後,為了更進一步觀察laminin a5與laminin g2對於癌細胞致癌力(tumorigenicity)的影響,我先將SAS細胞分成三組,一組為控制組,另兩組為laminin a5抑制組與laminin g2抑制組,分別以2×105個細胞注入免疫缺乏老鼠的皮下 ,並觀察與比較腫瘤的生長情形,實驗結果發現laminin a5抑制組或laminin g2抑制組的老鼠其身上長出的腫瘤平均大小明顯的比控制組小。由in vitro和in vivo的相關實驗結果顯示了抑制(knockdown)laminin a5與laminin γ2的表現確實會影響到癌細胞功能的改變,也使得癌細胞的生長能力顯著地被抑制,且也發現了laminin a5或laminin g2被抑制的口腔癌細胞在免疫缺失的老鼠身上有顯著較低的致癌能力,以上實驗結果與分析使我們更清楚了laminin a5與laminin g2在口腔癌腫瘤生成中所具有的重要性。
英文摘要 Oral squamous cell carcinoma (OSCC) has become the sixth most prevalent cancer in Taiwan, and the fourth prevalent cancer among men. Base on our laboratory’s previous data, we found that the percentage of cancer cells expressing integrin β1 became higher when the clinical stage became worse. Because laminins are important ligands for integrin β1, and previous studies revealed the correlation between laminins and cancers, my study was to investigate the relationship between the laminin g2 chain, laminin a5 chain and oral tumorigenesis. First I used immunohistochemistry to investigate their expressions on oral cancer patients; I found that laminin g2 chain and laminin a5 chain have higher expression levels in high-grade oral cancer tissues than in low-grade oral cancer tissues. Moreover, only a subpopulation of invading tumor cells show strong laminin g2 chain expression. By the western blotting and ICC staining, I also found that the protein levels of laminin g2 chain and laminin a5 chain in human tongue squamous-cell carcinoma cell (SAS) tumor sphere were dramatically increased compared to those of SAS monolayer. In addition, both laminin a5 and laminin g2 are important for oral cancer cell proliferation based on cell proliferation assay. Furthermore, the anticancer drug assays indicated that interference of laminin a5 and laminin g2 expression may influence the tumor microenviroment and lead to drug resistance. Many studies indicated that tumor sphere has more cancer stem-like cells. According to the above data, I proposed that the cancer cells expressing laminin g2 chain and laminin a5 chain probably have the characteristic of cancer stem cells (CSCs). I used shRNA to knockdown the expression of laminin g2 chain and laminin a5 chain, and tried to analyze the CSC markers in these knockdown cells by flow cytometry and IF staining. I found that laminin a5 chain is involved in the characteristic of oral cancer stem cell through indirect Oct-4 expression in cancer stem-like cell, and laminin g2 chain is involved in the characteristic of oral cancer stem cell through indirect CD44 expression in cancer stem-like cell. And I considered the roles of laminin a5 chain and laminin g2 chain in oral tumorigenesis are associated with the characteristic of oral cancer stem cell, since the characteristic of oral cancer stem cell is important to cancer cell tumorigenesis, but the mechanism of this results need to be further explored. And in the animal study, I found that knockdown of laminin a5 and laminin g2 reduced the tumorigenicity of the SAS cell in the NOD-SCID mice. According to the results of in vitro and in vivo, we could more understand the roles of laminin a5 and laminin g2 in the tumorigenesis of human oral cancer, I hope that the laminins could be a potential target for new biological therapies in the future.
論文目次 中文摘要 I
Abstract III
致謝 V
目錄 VI
圖目錄 IX
英文縮寫檢索表 XI
第一章 緒論 1
一、口腔癌概論 1
二、癌症幹細胞(Cancer stem cells) 2
1. 幹細胞與癌症幹細胞 2
2. 癌症幹細胞之鑑定標誌(markers) 4
三、細胞外基質(Extracellular matrix)概論 5
1. 細胞外基質簡介 5
2. 細胞外基質在癌症中的作用 6
四、層黏蛋白(Laminin)概論 8
1. Laminin簡介 8
2. Laminin與幹細胞的關係 8
五、研究動機 10
第二章 實驗材料與方法 11
一、免疫組織化學染色 (Immunohistochemistry;IHC) 11
二、SDS-PAGE蛋白質電泳 (SDS-PAGE protein electrophoresis) 13
三、西方點墨法 (Western blot) 15
四、免疫細胞化學染色 (Immunocytochemistry;ICC) 17
五、免疫螢光染色( Immunofluorescence staining;IF) 19
六、慢病毒的製備 (shRNA Lentivirus production) 20
七、慢病毒的感染 (Lentivirus infection) 20
八、細胞抗生素濃度測試 21
九、細胞培養 (Cell culture) 22
a. 繼代培養 (Subculture) 23
b. 冷凍保存細胞 (Freezing cells) 23
c. 解凍細胞 (Thawing cells) 24
d. 細胞計數 (Cell counting) 24
十、細胞蛋白質萃取 (Protein extraction) 24
十一、蛋白質濃度測定 (Protein assay) 25
十二、抽取質體 26
十三、洋菜膠體電泳 (Agarose gel electrophoresis) 27
十四、偵測細胞表面接受器 (Cell surface receptor detection) 28
十五、細胞生長分析 ( Cell proliferation assay ) 29
十六、動物實驗 (Animal model) 30
十七、統計分析 ( Statistics methods ) 30
十八、儀器設備 30
第三章 實驗結果 33
一、分析integrin β1和laminin γ2與laminin a5在人類口腔癌組織的表現………………………………………………………………………………33
二、比較integrin β1、lamininγ2與laminin a5在SAS單層細胞(monolayer)與SAS球體細胞(sphere)的表現 33
三、比較被抑制laminin γ2與laminin a5的口腔癌細胞SAS其在細胞功能上的差異 34
1. 利用shRNA轉染口腔癌細胞以抑制其laminin γ2與laminin a5的表現 34
2. 比較被抑制laminin γ2與laminin a5的SAS其生長能力的變化 34
3. 探討外加蛋白是否增加被抑制laminin γ2與laminin a5的SAS之生長能力 34
四、比較口腔癌細胞株的laminin表現量與癌症幹細胞標記(CSC             marker)的相關性 35
五、探討抗癌藥物對於laminin a5或laminin γ2受抑制之口腔癌細胞SAS的細胞毒性(cytotoxicity) 36
1. 分析5-Fluorouracil對於laminin a5或laminin γ2受抑制之口腔癌細胞SAS的細胞毒性 36
2. 分析Paclitaxel對於laminin a5或laminin γ2受抑制之口腔癌細胞SAS的細胞毒性 37
六、探討不同laminin受抑制後的口腔癌細胞注射在NOD-SCID老鼠後其腫瘤細胞的生長情形 38
第四章 實驗討論 39
第五章 結論 43
參考文獻 44
結果(附圖) 53
自述 67
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